Download Predominant Cerebellar Volume Loss as a Neuroradiologic Feature

AJNR Am J Neuroradiol 26:1675–1680, August 2005
Predominant Cerebellar Volume Loss as a
Neuroradiologic Feature of Pediatric Respiratory
Chain Defects
Fernando Scaglia, Lee-Jun C. Wong, Georgirene D. Vladutiu, and Jill V. Hunter
BACKGROUND AND PURPOSE: Predominant cerebellar involvement has not been previously reported as a common neuroradiologic feature in pediatric mitochondrial cytopathies.
Here we report the neuroradiologic findings of predominant cerebellar volume loss in children
with various mitochondrial disorders.
METHODS: A retrospective analysis of the medical records of 400 consecutive patients
referred for evaluation of mitochondrial encephalomyopathies was performed. In 113 cases,
definite diagnosis of mitochondrial disease was based on the modified adult criteria that
include clinical, histologic, biochemical, functional, molecular, and metabolic parameters.
RESULTS: Predominant cerebellar volume loss with progressive cerebellar atrophy and, less
often, cerebellar hypoplasia were found in a heterogeneous group of patients with mitochondrial
disease that consisted of four patients with complex I deficiency; four patients with multiple
respiratory chain deficiencies; two patients with combined complex I ⴙ III and II ⴙ III
deficiencies, including one patient with partial coenzyme Q10 deficiency; three patients with
complex II deficiency; two patients with complex IV deficiency; one patient with mitochondrial
neurogastrointestinal encephalomyopathy; and two patients with mitochondrial encephalomyopathy, lactic acidosis, and strokes.
CONCLUSION: Our retrospective study shows that isolated or predominant cerebellar
involvement can be found in various respiratory chain defects or mitochondrial disorders
expanding the classical neuroradiologic findings observed in mitochondrial encephalomyopathies. The diagnostic workup in patients with neuromuscular features whose brain MR imaging
exhibits cerebellar volume loss should include the evaluation for mitochondrial
encephalomyopathies.
Mitochondrial respiratory chain defects (RCDs) are a
heterogeneous group of disorders of energy metabolism that can present at any age, with a wide and
nonspecific range of clinical symptoms and with any
mode of inheritance, originating from any organ or
tissue, although tissues with high-energy requirements such as brain, skeletal muscle, and heart are
particularly vulnerable (1, 2). The diagnosis of RCD
can be particularly challenging to clinicians, especially
when patients are children, in whom nonspecific neurologic symptoms are common; the neuroradiologic
features may be atypical in the early stage, morphologic findings on skeletal muscle can be marginal, the
interpretation of the analysis of mitochondrial respiratory chain (RC) enzymes is often difficult, and mitochondrial DNA (mtDNA) defects are often absent
(3–5). Diagnostic criteria for pediatric RCD have
been modified from an adult classification system—
ie, the modified adult criteria (6). We previously studied the clinical course and outcome of 113 patients
with mitochondrial disease diagnosed by using these
modified criteria (7), representing one of the largest
published series concerning the pediatric age group.
Patients with mitochondrial disease often present a
combination of abnormalities from different patterns
on their MR imaging of the brain. Cerebral white
matter abnormalities in combination with lesions in
the basal ganglia and brain stem are relatively frequent (4, 8, 9). We identified these previously described MR imaging abnormalities in our cohort of
Received December 6, 2004; accepted after revision December
27.
From the Departments of Molecular and Human Genetics (F.S.)
and Radiology (J.V.H.), Baylor College of Medicine, and the Texas
Child Hospital (F.S.), Houston TX; and the Department of Pediatrics (G.D.V.), State University of New York at Buffalo, Buffalo,
NY.
Address correspondence to Fernando Scaglia, MD, Department
of Molecular and Human Genetics, Baylor College of Medicine,
and Texas Children’s Hospital, Clinical Care Center, Suite 1560,
6621 Fannin Street, Mail Code CC1560, Houston TX 77030.
© American Society of Neuroradiology
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Clinical, biochemical, molecular, and neuroradiologic findings of the patients
Patient/
Gender
Age at
Diagnosis
(months)
Presentation
RC/Molecular
Defect
Neurological
Symptoms
A, C, PR
A, C, H, HL,
PR, SZ
A, C, H, SZ
A, C, D, H, SZ
A, C, H, HL, SZ
C, H, PR, SZ
Cerebellar atrophy
Cerebellar atrophy
A, C, H, HL
A, C, H
A, C, H, SZ
A, C, H, HL, PR
A, C, H
A, C, H, HL
A, C, D, H, SZ
A, C, H, HL, SZ
A, C, H
Cerebellar hypoplasia
Cerebellar atrophy
Cerebellar atrophy
Cerebellar atrophy
Cerebellar atrophy
Cerebellar atrophy
Cerebellar atrophy
Cerebellar atrophy
Cerebellar atrophy/
bilateral basal ganglia
lesions
Cerebellar atrophy/
leukoencephalopathy
Cerebellar atrophy/stroke
like lesions
Cerebellar atrophy/strokelike lesions
1/F
2/F
295
67
NSME
NSME
CI–CIV
CI
3/F
4/F
5/F
6/F
85
20
7
85
NSME
NSME
NSME
NSME
7/F
8/M
9/M
10/M
11/F
12/M
13/M
14/M
15/M
13
48
31
45
162
35
31
43
16
NSME
NSME
NSME
NSME
NSME
NSME
NSME
NSME
LS
16/M
216
MNGIE
17/F
104
MELAS
CI
CI–CIV
CI ⫹ III, II ⫹ III
CI ⫹ III, II ⫹ III
(CoQ10 deficiency)
CI–CIV
CI
CI
CI
CII
CIV
CII
CII
CIV
SURF1
(Q195X/A56G)
TP (homozygous
IVS1-1G3C)
3243A3G
18/F
206
MELAS
3243A3G
A, H, O, P, PR
A, C, H, HL,
ST, SZ
A, C, H, HL, ST
MR Findings
Cerebellar atrophy
Cerebellar atrophy
Pontocerebellar hypoplasia
Mild cerebellar atrophy
Note.—CI through CIV indicates defect of the RC enzyme complex I to IV; CI–CIV, combined RC enzyme defects; CoQ10, coenzyme Q10; NSME,
nonspecific mitochondrial encephalomyopathy; LS, Leigh syndrome; MNGIE, mitochondrial neurogastrointestinal encephalomyopathy; MELAS,
mitrochondrial encephalomyopathy with lactic acidosis and strokelike episodes; A, ataxia; C, cognitive impairment; D, dystonia; H, hypotonia; HL,
hearing loss; O, external ophthalmoparesis; P, paresthesia; PR, pigmentary retinopathy; ST, strokelike episodes; SZ, seizures.
patients (7). In addition, we have identified a substantial number of patients with definite mitochondrial
disorders who exhibit cerebellar volume loss with either progressive cerebellar atrophy (in most patients)
and cerebellar hypoplasia. The cases presented here
definitely add RCD to the group of biochemically
and/or molecularly defined disorders that either
could cause progressive cerebellar atrophy or could
disrupt early cerebellar development causing cerebellar hypoplasia, expanding the spectrum of neuroradiologic features in patients with RCD.
Methods
The studies were approved by our institutional review board.
The diagnosis of mitochondrial disease was based on the use of
an objective classification scheme based on assigning major or
minor criteria for clinical, pathologic, enzymatic, molecular,
functional, and metabolic parameters (6). Patients with two
major or one major and two minor criteria were assigned with
a definite diagnosis and were included in the study (7). Evidence of at least two relatively independent types of investigations (ie, clinical, histologic, biochemical, or molecular) was
required to establish a definitive diagnosis. A muscle biopsy
was performed as part of the diagnostic evaluation in most
patients when a known pathogenic mtDNA mutation was not
identified in blood. Mitochondrial RC assays were performed
in 5% homogenates of frozen muscle specimens by using standard spectrophotometric assays (10 –13). Coenzyme Q10
(CoQ10) was analyzed in skeletal muscle by using high-performance liquid chromatography with ultraviolet detection (275
nm) and by using coenzyme Q9 as an internal standard (14, 15).
All patients were screened for mtDNA deletions/duplications
and common point mutations (MELAS A3243G and T3271C,
MERRF A8344G and T8356C, NARP T8993G and T8993C,
cardiomyopathy G8363A, and LHON G11778A, G3460A,
T14484C, and G14459A) (16, 17). Patients with a neurologic or
neuromuscular phenotype were examined by using MR imaging. The MR studies were performed by using a 1.5T unit
(Philips, Intera, Best, the Netherlands). T1-weighted images
were obtained in sagittal plane, and T2-weighted and FLAIRimages were obtained in axial and coronal planes. We specifically looked for changes in the signal intensity and size of the
basal ganglia and brain stem in T1- and T2-weighted images,
cerebral and cerebellar volume loss, focal lesions, and the stage
of myelination.
Results
Diagnosis of definite mitochondrial disease was
made in 113 patients (66 boys and 47 girls), ranging in
age from 2 weeks to 18 years of age. Sixty-eight
patients with predominant neuromuscular features
(70% of the cohort) who underwent brain imaging
studies had abnormal brain MR imaging findings.
After a careful retrospective review of neuroimaging
data by an experienced neuroradiologist, the findings
of this study in our group showed a wide spectrum of
abnormalities that included cerebellar and cerebral
atrophy, cerebellar hypoplasia, brain stem, and basal
ganglia lesions, infarct-like bilateral parasagittal lesions, agenesis of the corpus callosum, and white
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FIG 1.
Sagittal T1-weighted midline (A)
and coronal (B) T1-weighted MR images
through the posterior fossa show small cerebellar hemispheres and pontine hypoplasia
with prominent cerebellar folia.
FIG 2. A, Sagittal T1-weighted MR imaging demonstrates marked cerebellar volume
loss with good preservation of the pons. B,
Coronal T2-weighted sequence confirms
cerebellar but not cerebral atrophy.
matter abnormalities (7). Eighteen patients (26%)
exhibited predominant cerebellar volume loss with
the cerebrum less affected than the cerebellum. The
observed cerebellar volume loss included cerebellar
atrophy and cerebellar hypoplasia (Table 1). Two
patients exhibited cerebellar hypoplasia (patients 5
and 7; Table 1), whereas the remainder exhibited
progressive cerebellar atrophy. All of these patients
had early neurologic findings with a mean age of
symptom onset of 5 years. Cerebellar ataxia was the
presenting feature in all but one patient (patient 6;
Table 1). The average time from symptom onset to
MR imaging was 3 years.
Patients with a Nonspecific Mitochondrial
Encephalomyopathy
Fourteen patients with predominant cerebellar involvement and different RC defects of 30% or less
of residual enzymatic activity on skeletal muscle, had
a nonspecific mitochondrial encephalomyopathy
(NSME) with neurologic symptoms ranging from psychomotor retardation, seizures, hypotonia, hypertonia, and sensorineural hearing loss, to ophthalmologic features such as pigmentary retinopathy, and
external ophthalmoparesis. Thirteen patients among
this group exhibited cerebellar ataxia and one of
them, who had combined RCD, also exhibited
marked dystonia (patient 4; Table 1). The one patient
who did not present with cerebellar signs had com-
bined complex I ⫹ III and II ⫹ III deficiencies, mild
cerebellar atrophy, and a 50% reduction in the skeletal muscle CoQ10 content consistent with partial
CoQ10 deficiency (patient 6; Table 1). One patient
with isolated complex I ⫹ III and II ⫹ III deficiencies
and predominant neurologic features including psychomotor retardation, ataxia, seizures, hypotonia,
corneal opacity, and sensorineural hearing loss (patient 5; Table 1) exhibited pontocerebellar hypoplasia
(Figs 1A and -B), and a second patient with combined
RC defects and hypotonia, ataxia, developmental delay, sensorineural hearing loss, and pigmentary retinopathy (patient 7; Table 1) displayed isolated cerebellar hypoplasia and good preservation of the pons
(Figs 2A and -B). The latter patient later developed a
hypertrophic cardiomyopathy and renal tubular acidosis. The rest of the group exhibited progressive
cerebellar atrophy (Figs 3A–C). Figure 3 exhibits an
example of progressive cerebellar atrophy as mentioned in the text.
Leigh Syndrome and Cerebellar Volume Loss
The diagnosis of Leigh syndrome (LS) was made in
one patient of our cohort (patient 15; Table 1) who
exhibited cytochrome C oxidase deficiency in skeletal
muscle and fibroblasts and was compound heterozygote for two mutations (Q195X/A56G) in the SURF-1
gene. Before the development of focal bilateral lesions in the basal ganglia, this patient was found to
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FIG 3. Sagittal midline T1-weighted (A) and coronal fluid-attenuated (B) inversion recovery (C) images demonstrate evidence of
progressive cerebellar atrophy when compared with interval sagittal T1-weighted midline image. Note evidence of pontine involvement
with T1-weighted hypointensity returned from a pons diminished in size.
have predominant cerebellar atrophy on brain MR
imaging and clinically, psychomotor retardation, hypotonia, and cerebellar ataxia.
Mitochondrial Neurogastrointestinal
Encephalomyopathy
The patient reported with mitochondrial neurogastrointestinal encephalomyopathy ([MNGIE] patient
16; Table 1) had a classical clinical presentation,
including gastrointestinal dysmotility, ptosis, and peripheral neuropathy, but without skeletal muscle involvement at morphologic, enzymatic, or mitochondrial DNA level, although gastrointestinal myopathy
was present. The patient was homozygous for a novel
thymidine phosphorylase gene (TP) splice acceptor–
site mutation, IVS1–1G3 C (18). MR imaging of the
brain showed leukoencephalopathy, although the patient also exhibited predominant cerebellar volume
loss with cerebellar and cerebral atrophy.
Mitochondrial Encephalomyopathy with Lactic
Acidosis and Strokelike Episodes
The two patients with mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes
(MELAS) in our group (patients 17 and 18; Table 1)
had the common 3243 A3 G mutation in the mt
tRNALeu gene with 30% and 43% heteroplasmy in
peripheral blood, respectively. Both exhibited a typical clinical presentation with strokelike episodes preceded by seizures and accompanied by pancreatitis
and diabetes mellitus in one of them (patient 18;
Table 1). Extensive infarct-like lesions, not confined
to vascular territories were present in these patients
and cortical atrophy was observed. Both patients,
however, also exhibited significant and marked progressive cerebellar atrophy.
Discussion
Different patterns of brain MR imaging abnormalities have been recognized and described in patients
with mitochondrial disease (4, 8, 9). They comprise a
pattern of energy failure, consisting of cortical
pseudoinfarcts, basal ganglia lesions, and brain stem
lesions in the acute phase as typically seen in
MELAS, LS, and NARP; a second pattern of chronic
neurodegeneration with global cerebral and/or cerebellar atrophy as observed in MERRF; a third pattern
that consists of focal and diffuse white matter abnormalities, often with cystic degeneration and areas of
contrast enhancement as observed in complex I, complex II, and complex IV deficiencies, and MNGIE;
and, finally, a pattern of malformations that may be
seen in severe variants of pyruvate dehydrogenase
complex deficiency.
In our cohort, most of the patients with predominant cerebellar volume loss presented clinically with
an unspecified encephalomyopathy with neurologic
symptoms that ranged from developmental delay to
seizures. Most of these patients had cerebellar ataxia,
dysmetria, and dysdiadokokinesis, although one patient was not found to have cerebellar features. Classical mitochondrial syndromes in our pediatric group
were uncommon as they occur more often in adults
(19).
As previously mentioned, the patients with
MELAS, LS and SURF1 deficiency, and MNGIE
exhibited patterns in their brain imaging studies that
have been previously described; however, they also
displayed considerable cerebellar involvement, which
was more predominant than cerebral atrophy and
other features observed on their brain MR imaging
studies.
MNGIE is defined as an autosomal recessive disorder caused by mutations in TP (20). Clinical diagnostic criteria have been established for MNGIE:
severe gastrointestinal dysmotility, cachexia, ptosis,
external ophthalmoparesis, peripheral neuropathy,
and leukoencephalopathy (21). Leukoencephalopathy has always been described as the main neuroradiologic feature of patients with MNGIE (22); however, cerebellar atrophy has not been previously
reported as a predominant neuroradiologic finding in
AJNR: 26, August 2005
addition to leukoencephalopathy, as observed in our
case.
MELAS is characterized by strokelike episodes
preceded by seizures. Short stature, diabetes mellitus,
hearing loss, and slowly progressive mental impairment are common features (23). The most common
mtDNA point mutation occurring in this syndrome is
an A3 G transition at the tRNALeu (UUR) 3243,
which causes a defect in mitochondrial protein synthesis (24).
Cerebellar atrophy in the context of MELAS has
been described elsewhere (25). Enlargement of the
4th ventricle was the first sign of cerebellar atrophy,
which was present only with severe disease, according
to a previous publication (25). Although enlargement
of the 4th ventricle was not detected in our patients
with MELAS as a first sign of cerebellar atrophy, the
demonstrated progressive cerebellar atrophy at a severe stage of the disease corroborates previous findings by Sue et al 1998 (25). These findings likely
reflect a distinct disease process in MELAS, that of a
slowly progressive degenerative process causing cerebellar as well as cerebral atrophy.
LS presents clinically as an early-onset progressive
neurodegenerative disorder with a characteristic neuropathology consisting of focal, bilateral lesions in
one or more areas of the central nervous system—
including the brain stem, thalamus, basal ganglia,
cerebellum, and spinal cord—accompanied by progressive impairment of cognitive and motor function,
leading to loss of respiratory control and death in a
few months or years (26). In recent years, deficiencies
of pyruvate dehydrogenase complex, complexes I, II,
and IV deficiencies, high levels of the T8993G mutation in the mtDNA ATPase 6 gene, and SURF1 mutations have been described as causes of LS (27).
Brain MR imaging may demonstrate areas of altered
signal intensity in the brain stem, cerebellum, and
basal ganglia. Our patient with LS due to cytochrome
C oxidase–associated SURF deficiency displayed progressive cerebellar atrophy and ataxia as presenting
features. This presentation is quite uncommon and
has been described elsewhere by Cacic et al (28), who
reported a 2.5-year-old patient who presented with
ataxic gait and tremor and developed an extrapyramidal syndrome with a head CT revealing marked
cerebellar involvement. These cases demonstrate that
marked cerebellar involvement can predate other
neuroradiologic features of LS.
Although cerebellar involvement has been described as part of a wider array of central nervous
system abnormalities in patients with mitochondrial
disorders (4, 8, 9, 29), predominant cerebellar involvement (atrophy or hypoplasia) has not been commonly described as a significant neuroradiologic feature in children with mitochondrial RCD. One
exception would be the cerebellar atrophy affecting
both cerebellar hemispheres and vermis, observed in
the ataxic syndrome caused by primary CoQ10 deficiency, a mitochondrial encephalomyopathy associated with deficiencies of quinone-dependent enzymes
(complex I ⫹ III and II ⫹ III) and responsive to
PEDIATRIC RESPIRATORY CHAIN DEFECTS
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CoQ10 supplementation (30). One of the two patients
with observed combined complex I ⫹ III and II ⫹ III
deficiencies had mild cerebellar atrophy on MR imaging and manifested a partial deficiency of the quinone pool. The observed mild degree of atrophy
could explain the absence of cerebellar symptoms in
this patient. The mechanism responsible for the selective and progressive cerebellar atrophy in primary
CoQ10 deficiency is not entirely known. In one study
(31), the regional distribution of coenzyme Q10 in the
brain of adult rats was investigated. The results
showed that in rats the cerebellum contained the
lowest level of CoQ10 of the seven brain regions that
were investigated. Of the four regions of one human
brain studied in the same paper, the cerebellum exhibited the lowest CoQ10 concentration. The investigators hypothesized that there could be a selective
vulnerability of the cerebellum to a potential depletion of the quinone pool.
The neuroradiologic and biochemical findings in
the patients in our series, however, demonstrated that
predominant and progressive cerebellar atrophy
could be associated mostly with other types of RCD
or mitochondrial syndromes, expanding the spectrum
of mitochondrial disorders associated with it. The
etiology of this predominant cerebellar over cerebral
involvement observed in such a heterogeneous group
of patients remains unknown as of yet. We speculate
that the specificity of pathogenic involvement of the
cerebellum observed in this diverse group of mitochondrial disorders could be due to the result of the
tissue-dependent expression of the underlying molecular and biochemical disorder. A population of neuronal mitochondria in the cerebellum could be more
vulnerable to oxidative stress resulting from mitochondrial dysfunction in some patients with mitochondrial disorders because, as previously stated, the
cerebellum exhibits the lowest concentration of
CoQ10.
Although, for the most part, the patients in our
cohort exhibited isolated cerebellar atrophy, two patients with RCD in our group exhibited cerebellar
hypoplasia. Few cases of cerebellar hypoplasia and
associated RCD have been previously described. A
patient with a mitochondrial encephalomyopathy that
presented with severe hypotonia, myoclonic seizures,
and optic atrophy due to cytochrome C oxidase deficiency and hypoplasia of the cerebellum with rudimentary cerebellar hemispheres has been described
elsewhere (32). Moreover, de Koning et al reported a
case of lethal pontocerebellar hypoplasia associated
with multiple RCD in skin fibroblasts (33). The cerebellum develops early in the first trimester of pregnancy, and anatomic differentiation of the major divisions of the cerebellum is completed within the
first trimester (34). These previous reports in addition to our results suggest that ATP production
and the biosynthetic pathways depending on a functional RC are crucial in a critical period of cerebellar differentiation.
In summary, the diagnostic work-up in patients
with psychomotor retardation and neuromuscular
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features including early onset of cerebellar ataxia and
predominant cerebellar involvement on brain MR
imaging should include the search for mitochondrial
disease. Even in disorders such as LS, caused by
SURF1 mutations and associated with cytochrome C
oxidase deficiency, progressive cerebellar volume loss
may be the first neuroradiologic feature observed. In
retrospect, because some of the patients of our cohort
were ascertained in childhood rather than in early
infancy, it is not possible to completely determine
whether the cerebellar involvement is due to impaired differentiation leading to cerebellar hypoplasia, or merely progressive atrophy. Thus, a prospective volumetric study in our group will help us to
better understand the different types and prevalence
of cerebellar volume loss in disorders of energy
metabolism. MR spectroscopy might also assist in demonstrating different patterns of metabolic change reflecting different substrates of neuronal mitochondrial
activity leading to cerebellar volume loss.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Acknowledgments
22.
We thank the Baylor College of Medicine Mental
Retardation Research Center for its support.
23.
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